SUMMARY Sepsis is a clinical syndrome that complicates severe infection. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. There are no specific FDA-approved medicines for the treatment of sepsis. Current concepts of the pathophysiology of sepsis suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of the immune system. This manifests as an inability to control bacterial growth and dissemination, and excessive inflammation, processes that are interrelated and are due, in a large part, to dysfunction of both the adaptive and innate immune systems. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A2A adenosine receptors (ARs) on the surface of immune cells. A2AAR signaling reproduces many of the phenotypic changes in immune cells that are characteristic of sepsis, including T helper lymphocyte deactivation and exhaustion and diminished ability of monocytes and macrophages to ingest and kill bacteria and other sepsis-causing pathogens. Given this similarity between septic immune alterations and the ones caused by A2AAR signaling, we hypothesized that endogenous adenosine would contribute to the sepsis-induced onset of immune dysfunction via stimulation of A2AARs. Our preliminary data using both targeted genetic deletion and pharmacological antagonism have confirmed that A2AARs contribute to both septic immune dysfunction and mortality in mice. We thus propose to develop A2AAR antagonists for the management of patients with sepsis. We have synthesized two novel, highly potent and selective A2AAR antagonists, TP412 and TP455, which we will test for efficacy in preventing septic mortality. The Specific Aim of the proposal is to assess the effect of TP412 and TP455 on mortality in murine sepsis. We expect that TP412 and TP455 will reduce mortality in septic mice. The long-term goal of this study is to develop TP412 and TP455 as safe and effective treatment options for the management of patients with sepsis.